The long-term objective of this grant is to increase our understanding of the fundamental features of fluoride metabolism with special emphasis on the impact of acid-base status on the overall process. During the first six years of grant-related work, it has been learned that urine pH is a major determinant of the rate of fluoride removal from the body. Changes in this variable are reflected in the amount of fluoride retained in the plasma, soft tissues, bones and teeth. It is now evident that the distribution of fluoride between the extracellular and intracellular fluids of some tissues is a function of the magnitude of the transcellular pH gradient. These findings have contributed to our understanding of the cariostatic effect of fluoride and have suggested new ways to alter the amount of fluoride in the body generally or in selected tissues. The studies proposed for the next three years will expand on these findings. The influnce of the acidity of solutions contained in the stomach on the rate of fluoride absorption, peak plasma levels, the time course of plasma fluoride levels, and on tissue fluoride concentrations and fluoride balance will be determined. The effects of the rate of gastric acid secretion on these variables will also be determined in both acute and chronic studies. Studies on the possibility of "active" fluoride transport by the intestine will be done using the everted sac technique. The possible involvement of plasma fluoride levels in the regulation of fluoride absorption from the GI tract, as claimed in the literature, will be tested. In an effort to better understand the damaging effects of high fluoride levels on the gastric mucosa, the ability of gastric mucosal cells to accumulate fluoride will be determined. In addition, further studies on the mechanism of fluoride distribution between plasma and red blood cells will be done using imposed PH gradients and specific inhibitors of the red cell anion transport system. The influence of the acid-base status of the gravid animal on the fluoride levels of neonatal tissues will be determined. Finally, the interplay between the renal and extrarenal clearances of fluoride will be evaluated in terms of the age of the animal and the dosage schedule suing pharmacokinetic techniques.